Manufacture of derivatives of 4-hydroxypiperidines and process of making same



I 20 and the new products of the formula 65 Rcacidyl residue? R =H or alkyl,; aryl,

Patent 29 1925;

umrno stares 'mm oriucn.

S'L'AUDINGER, F ZURICH, SWITZERLAND, ASSIGNOE CEO SOCIETY O1". INDUSTRY IN BABLE, 0F BASED, SWITZERLAND.

mun-Lorene or nnnrvarrvns or emnoxrmrnnmmns m1) rnecnss or MAKING sum.

in Drawing. Application filed Hatch as, 1925. Serial No. iansa same time be H and the sum of carbon atoms in R and R is more than 1.

The 2.6 dimethyl-N-methyl4-hydroxypiperidine diflers from tropine only in that it lacks the pyrrolidine ring (see German specification No. 292,871).

It may therefore be regarded as an open To'all wk'om'z't may concern:

Be it known that I, HERMANN STAU- nmenn, a citizen of the Swiss Confederation, and residing at Zurich, Switzerland,

5 have invented new and useful Improvements in the Manufacture of Derivatives ofl-Hydrox piperidines and Processes of :Makmg ame, of which the following is a chain tropine:

full, clear, and exact specification. CWHAJ w The present inventlon relates to derivaanon on tives of -hydroxypiperidmes of the formula P- CHr-C -cn I Open chaintropine. A n -o Compounds of this or a similar kind have lit-N already been described in literature. They are obtained by reducing the corresponding pyridine derivatives; The esterification of these open chain tropines produces substances which are medicaments.

According ,to this invention, such open chain tropine derivatives are produced in I ghuite a new manner by converting a 'allylcarbinol ester or a substitution product thereof into its dihydrohalide and treating the latter with ammonia or an aliphatic, aromatic or aliphatic-aromatic primary wherein B=a1ky1 and R -H, alkyl, aryl, aralkyl, and R :..H or acidyl. It comprises the. process of manufacture thereof n-on nrgggm ynom wherein A and -B=alkyl, Raf-1H, allkyl, a l aralkyl R=H orraciy an in and R cannot at the amine.

oHPcn-o om-onns-o om-oH-cn nom mr non Nina Br-N cnox oHi-On-o om=omn-o om-ds-cn jected to a purification by re-precipitation or crystallization.

According to .the kind of diallylcarbinol. ester used for the condensation, the 0 en chain tro. ine ester obtained is more or are stable. carbinolacetate there is obtamed the corresponding open chain tropine acetate .which even at'thetemperature neceesaryfor ring closure is .inpart saponified to freeopen chain tropinet For the purpose of comp eting the saponification the mixture produced by the reaction may be heated with a dilute solution of caustic potash. The aromatic acid esters of the o 11 chain tropines are much more stable. carbinol ester, therefore, it is possible to ob tain in a single reaction either the open chain tropine-esier, or, in preponderance, thefreetropine. Inanycaeetheestermly lalkyl; X=H or R. he diallylcarbinol esters which serve as parent materials, can ,be obtained by the process: of Saytzefl, Liebigs Annalen 185 no" (1877), page 129. By treatin these with:

hydrogen halide, the dihydro alide addition E-products are obtained. Stereoisomerides are produced and can be separated by crystallization. .By the action of amct monia. or a primary amine on the dihydro halide of the diallylcarbinol ester, if necessary in presence of an indifferent solvent, 'the-pipendine ring closure occurs. The reaction is advantageously accelerated by 10' gentle heating. j The hydrohalides of the esters of the corresponding. open, chain tropines separateafter. the condensation in either solid or hqnid condition and are preferably eubor instance, starting from diallyly selecting the dia1lyl= I be converted into the free tropine by saponification with alkali.

The following examples illustrate the invention:---

Ewample 1.

Adopting a process which is a variation of Saytzefis, 760 grams of allylbromide, 220 grams of formic acid ethyl ester are caused to react with 400 grams of zinc filings in presence of 800 cc. of absolute ether. Then one gram molecule of benzoic acidanhydride is caused to react on the mixture so that the benzoate of diallylcarbinol is obtained; this is purified by distillation in a vacuum, an is then converted into its dihydrobromide by treatment with two gram molecules of hydrogen bromide in solution of 30 per cent strength in glacial acetic acid. Three stereoisomerides of this dihydrobromide are possible; one of them melts at 7678 C. and can easily be isolated by treatment with petroleum ether.

These dihydrobromides, either in'crude unseparated condition or after separation when in a pure state, are caused to react with two gram molecules of a primary base in the presence of-twice the volume of benzene or toluene, with exclusion of water and at 80100 C. After about to 1 day reaction is complete, and if pure parent materials have been used the hydrobromide of the benzoate separates as a crystalline mass together with the hydrobromide of the primary base. On the other hand, if the mixture of the stereoisomerides is used, the separated mass of salts generally does not crystallize.

For example, if methylamine is used in the reaction. the hydrochloride of the henzoate of 2.6-dimethyl-N-=methyl4-hydroiperidine is obtained as a white crystalline powder, which melts at 201203 C. The free benzoate is liquid and boils at 170-173 C. at 13 mm. pressure.

The nhenylethyl derivative is obtained by the action of phenylethylamine with the hydrobromide of diallylcarbinol benzoate in form of its hydro-bromide, which constitutes a wh te crystalline powder, sparingly soluble in water and melting at 225 C. The hydro-' chloride is also a white crystalline powder melting at l91-193 C.

The hydrohalides of the benzoates are generally less soluble in water than the corresponding salts of the primary base used for the reaction, and may thus be separated from the latter by treatment with cold water.

Usually it is not necessary to isolate the free esters, since the aqueous solutions of the hydrohalides of the esters are used.

If the separated salts do not crystallize the components of the mixture cannot be separated by fractional distillation; in "1 case,

aeeaaoo the primary, base may be separated by liberating it together with the tropine ester by addition of caustic soda lye and separating the more volatile primary base from the tropine ester by distillation in a vacuum.

Example 2.

3 molecular proportions of anhydrous methylamine are heated in about 2 parts of benzene or toluene with 1 molecular roportion of the dihydrobromide of dial lcarbinolacetate for 3 hours at 80-90 'C. eaction occurs with piperidine ring closure.

The mass of salts which separates is a mixd ture of the hydrobromi'des of the N-methyl- 2.6-dimethyl-4-hydroxypiperidine and its acetate. From this mixture the free base may be isolated by saponification with caustic potash solution of 10 per cent strength, extraction'with ether and distillation in a vacuum. The pure substance melts at 89.5- 90.5 C. By treatment with sodium amylate a stereoisomeride can be obtained as in the case of tropine; this is liquid and boils at 106-108 C. at 12 mm. pressure.

In similar manner there may be obtained, b using, instead of methylamine, alcoholic ammonia, the 2.fi-dimethyll-hydroxypiperidine (open chain Nortroperin), melting at 132-133 C., with allylamine the N-allylderivative, melting at 4849 (1., and with phenylethylamine the N-phenylethyl-derivative melting at 8587 C.

Instead of the benzoates and acetates of diallylcarbinol other esters, ii. the mandelic ester, and instead of the amines named above other primary amines, ii. ethylamine or its homologues, further aniline, benzylamine and other aliphatic, aromatic, or aliphaticaromatic amines may be used.

What I claim is:

1. Process for the manufacture of derivatives of 4-hydroxypiperidines by converting a diallylcarbinolester into its dihydrohalide and condensing the latter with a base of the formula NH R wherein R=H, alkyl, aralkyl or aryl.

2. Process for the manufacture ofderivatives of 4-hydroxypiperidines by converting a diallylcarbinolester into its dihydrohalide and condensing the latter with a base of the formula NH.,R wherein -R:H, alkyl, aralkyl or aryl, the condensation being conducted in presence of an indifferent solvent.

3. Process for the manufacture of derivatives of 4-hydroxypiperidines' by converting a diallylcarbinolester into its dihydrohal de and condensing the latter with a base of the formula NH.,R wherein R=H, alkyl, aral lryl or aryl, the condensation being conducted with gentle heating.

4. Process for the manufacture of derivatives of l-hydroxypiperidines by converting a diallylcarbinoles'ter into its dihydrohalide has a ee'aaoe and condensing the latter with a base of the formula NH R wherein R=H, alkyl, aralkyl or aryl, the condensation being conducted in presence of an indifferent solvent and with gentle heating.

51 Process for the manufactureof derivatives of 4-hydroxypipericlines by converting a diallylcarbinolester into its clihydrohalide condensing the latter with a base of the formula NH R wherein R=H, alkyl, arallzyl or aryl, and saponifying the product thus ohtained,

6. Process for the manufacture of derivatives of 4-hydroxypiperidines by converting a diallylcarbinolester into its dihydrohalid'e and condensing the latter with phenylethylamine in presence of an indifierent solvent and with gentle heating. a

7. Process for the manufacture of derivatives of l-hydrox ypiperidines by conveiting diallylcarbinolbenzoate into its dihydrohalide and condensing the latter with phenylethylamine in presence of an indill'erent solvent and with gentle heating.

8. As new products the herein described derivatives of 4-hyclroxypiperdines of the general formula:

CH-CH B wherein A and B alkyl, s ar, alkyl,

esters of thyolrooaypiperidines of the general formula: 4

011-011 Ill-N;

B wherein A and B alkyl, R zltl, alkyl, aryl or arallryl, lt zacidyl. k 10. As new products the herein described esters of ethydronypiperidines of the general formula:

OHORI CH-CHr R1-N UHOR:

- CH-CH CH CHr Biz-H, allayl, aryl or arallryl.

12. new product the herein described loenzoate oi 2.6-dimethyl hhphenylethyl-t hydroxypiperidine of the formula OH-UHm Ha which terms with hydrohalides crystalline salts, sparingly soluble in water, the hydrobromide melting at 225, the hydrochloride at Ell-193.

In witness whereof I have hereunto signed my name this 14th (lav of March, 1925.

HERMANN STAUDINGER.

CHOCOCaHs 

